Aging, Burn Trauma, and Liver Damage

PROJECT SUMMARY This proposal investigates why burns cause more severe liver damage in older individuals and devises an innovative treatment strategy to counter this damage alongside a novel diagnostic approach for earlier detection. This endeavor is crucial given the significantly higher mortality rate in older burn victims compared to

younger patients, necessitating age-specific interventions. Burn injuries have been found to affect multiple organs, including the liver, which is highly susceptible to damage due to its unique structure and blood supply. This project focuses on burn-induced liver damage, a well-documented yet untreatable issue particularly

prevalent in elderly populations. Our proposed studies investigate the role of MCJ (Methylation-controlled J protein), a protein that negatively regulates mitochondrial metabolism in hepatocytes (liver cells) following burn injuries in aged mice. We particularly focus on age-related factors such as increased production of pro-

inflammatory cytokines, which can modulate mitochondrial respiration and potentially cause liver injury. This innovative approach will employ state-of-the-art methods for diagnosing mitochondrial respiratory dysfunction and oxidative damage, as well as assessing liver function. Our preliminary data show increased MCJ

expression in the livers of aged mice postburn in settings of heightened age-related hepatic inflammation. Furthermore, in vivo MCJ silencing in hepatocytes of aged mice reduced postburn mortality. From these observations, we hypothesize that the inflammatory response after burn injury in aged subjects upregulates

MCJ expression in hepatocytes, leading to reduced mitochondrial respiration and subsequent liver damage and dysfunction. We also predict that therapeutic silencing MCJ in hepatocytes can be a novel strategy to attenuate the aberrant hepatic response to burn in older subjects. To test this hypothesis in Aim 1, we will

investigate how MCJ alters mitochondrial respiration in hepatocytes of aged mice postburn, potentially leading to liver damage. In Aim 2, we will examine the role of pro-inflammatory cytokines, specifically tumor necrosis factor-α (TNF-α) and interleukin-1beta (IL-1β), on postburn mitochondrial respiratory dysfunction and MCJ

upregulation. Lastly, in Aim 3, we will explore a novel liver-focused treatment using small interfering RNA conjugated with N-acetylgalactosamine (GalNAC-siMCJ) for reducing postburn liver damage in aged mice by silencing MCJ specifically in hepatocytes. In parallel, we aim to evaluate the potential of MCJ (DnajC15) mRNA

serum levels as a biomarker of liver damage in burn patients. This proposal holds transformative potential in human health, particularly for aging burn victims. By innovating therapeutic approaches, we aim to significantly reduce mortality rates and improve prognoses. Additionally, considering the heightened vulnerability of the

elderly population to liver diseases, our research could drastically affect a broad spectrum of liver pathologies. Essentially, our work seeks to unravel the complex interplay between age, burns, and liver damage, laying a solid foundation for pivotal future research and clinical applications.